1. HEPATIC CLEARANCE Q x CA Q x CV Q(CA - CV) 1. Mass Balance
Rate of Extraction

2. HEPATIC CLEARANCE 1 E 1 - E Extraction Ratio
2. Mass Balance Normalized to Rate of Entry 1
1 - E E
Extraction Ratio

3. HEPATIC CLEARANCE Q Q x E Q(1 – E) Clearance
3. Mass Balance Normalized to CA Q
Q(1 – E)
Q x E
Clearance

4. Recall that CL = QE; hence
CLH = QHE
CLH = hepatic clearance
QH = hepatic blood flow
E = hepatic extraction ratio
QH - from 1.0 to 1.5 L/min
E – ranges from 0 to 1

5. Recall that CL = QE; hence
CLH = QHE
Thus, if the non-renal clearance of a drug exceeds QH, some form of non-renal and non-hepatic elimination must take place.

6. Example: (labetalol)
CLT = L/min
CLR = 0.08 L/min
Vss = 685 L
t1/2 = 6 hr
Can the nonrenal clearance be attributed solely to hepatic elimination?

7. CLH = QHE
Suggests that
CLH ~ QH
Actually
h QH = i E

8. VENOUS EQUILIBRIUM MODEL
QCin
QCout
Elimination

9. SINUSOIDAL MODEL
QCin
QCout
Elimination

10. Intrinsic hepatic clearance: The ability of the liver to remove xenobiotic from the blood in the absence of other confounding factors (e.q., QH).

11. Since
CLH = QHE

13. Quantitative Assessment of Hepatic Clearance Assuming the Venous Equilibrium Model

16. Limits:

17. Limits:

19. Limits:

20. Limits:

21. Compounds with a high CLint, are said to exhibit perfusion rate-limited elimination.

22. From: Rowland M, Tozer TN
From: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edition, 1995, p. 162

23. HEPATIC EXTRACTION RATIO OF REPRESENTATIVE DRUGS
Low (<0.3)
Antipyrine
Diazepam
Phenylbutazone
Theophylline
Tolbutamide
Warfarin
High (>0.7)
Lidocaine
Meperidine
Propoxyphene
Propranolol
Verapamil
Intermediate: Quinidine

24. CLint = 7.0 L/min, QH = 1.0 L/min Ko = 1.0 mg/min
Consider the case of administering a constant infusion of a drug with the following conditions:
CLint = 7.0 L/min, QH = 1.0 L/min
Ko = 1.0 mg/min
Assuming drug is eliminated completely via hepatic metabolism, what would the steady-state concentration be?

26. What if the pt developed CHF resulting in a 25% reduction in QH?

27. CLint = 0.01 L/min, QH = 1.0 L/min K0 = 0.1 mg/min
In contrast, suppose we administer a low CLint?
CLint = 0.01 L/min, QH = 1.0 L/min
K0 = 0.1 mg/min

28. What if QH were reduced by 25%

29. FIRST-PASS EFFECT
LIVER
BODY
HEART
GUT

30. LIVER
BODY
HEART
GUT

31. LIVER
BODY
HEART
GUT

32. LIVER
BODY
HEART
GUT

33. LIVER
BODY
HEART
GUT

34. LIVER
BODY
HEART
GUT

35. If a drug is completely absorbed after oral administration, the fraction of the oral dose that reaches the systemic circulation (F) is given as
F = 1 - E
Remembering that

36. QH >> CLint, Fg1
QH << CLint, Fg0

38. Determination of CLint after oral dosing:
Assumes:
Drug is completely absorbed
No extrahepatic metabolism
System is stationary

39. Determination of CLint after oral dosing:

40. Determination of CLint after oral dosing:

41. Estimated in this fashion the CLint is often referred to as the oral clearance (CLo)
For a high CLint drug:

42. Estimated in this fashion the CLint is often referred to as the oral clearance (CLo)
For a low CLint drug:

43. Consider a high clearance drug (e. g
Consider a high clearance drug (e.g., propranolol) after oral and IV dosing:
CLint = 10 L/min, QH = 1.5 L/min

44. What if drug were administered orally under these conditions?
What would happen to CLH is QH were reduced to 1.0 L/min?
What if drug were administered orally under these conditions?

46. How would a decrease in QH affect this?

47. But what happens to AUC?
For control conditions:
When QH is decreased:

48. IMPACT OF PROTEIN BINDING
CLint = fubCLuint

50. Effect of protein binding on warfarin clearance in the rat
Effect of protein binding on warfarin clearance in the rat . Data from Yacobi A, Levy G. J Pharm Sci 64:1660, 1975.

51. Effect of protein binding on warfarin clearance in humans
Effect of protein binding on warfarin clearance in humans. Data from Routledge et al. Br J Clin Pharmacol 8:243, 1979.

52. CLuint = 0.25 L/min QH = 1.5 L/min
fub = K0 = 0.25 mg/min

53. CLuint = 0.25 L/min QH = 1.5 L/min
fub = K0 = 0.25 mg/min

54. What if fub = 0.2?

55. What if fub = 0.2?

56. What happens to free concentration?

57. What about oral administration?

58. Consider a high clearance drug iv:
CLuint = 30 L/min QH = 1.5 L/min
fub = K0 = 2 mg/min

59. Consider a high clearance drug iv:
CLuint = 30 L/min QH = 1.5 L/min
fub = K0 = 2 mg/min

60. What if fub = 0.5?

61. What if fub = 0.5?

62. What about oral administration?

63. What if fub = 0.5?

64. What if fub = 0.5?

65. Effect of displacement (D) of plasma protein binding on total and unbound concentrations of drug
From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition

66. From: Rowland M, Tozer TN
From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition

67. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0 E
CLint L/min
CLH L/min
0.18
0.334 L/min
0.273 L/min
Blood Concentration
0.1
Time

68. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
Blood Concentration
0.1
Time

69. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0 E
CLint L/min
CLH L/min
0.95
27.0 L/min
1.42 L/min
Blood Concentration
0.1
Time

70. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
0.1
Blood Concentration
0.01
Time

71. Effect of rifampin on the kinetics of warfarin after a single dose before (open circles) and after (closed circles) treatment with rifampin 600 mg/day. From: O’Reilly RA. Interaction of sodium warfarin and rifampin. Ann Intern Med 81:337-40, 1974.

73. Effect of pentobarbital on alprenolol disposition
Effect of pentobarbital on alprenolol disposition. Alprenolol was administered before (O, closed, iv, open oral) and after 10 d of pentobarbital (D). Reproduced from Alvan G, et al. Clin Pharmacol Ther 22: , 1977.

74. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0 E
QH L/min
CLH L/min
0.18
0.75 L/min
0.135 L/min
Blood Concentration
0.1
Time

75. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
Blood Concentration
0.1
Time

76. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0 E
QH L/min
CLH L/min
0.95
0.75 L/min
0.71 L/min
Blood Concentration
0.1
Time

77. Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
0.1
Blood Concentration
0.01
Time

78. Propoxyphene’s CNS depression is enhanced when co-administered with ethanol. To assess the contribution of a pharmacokinetic interaction to this enhancement, propoxyphene was administered iv and po, with and without ethanol. The curves below illustrate the results. What is the mechanism of interaction?
Propoxyphene alone
Propoxyphene + ETOH
Log [Propoxyphene]
Log [Propoxyphene]
TIME
TIME

79. CLH AUCo fup fup Complete the following graphs for a drug with a
CLH = 20 mL/min/kg and one with a
CLH = 1 mL/min/kg
CLH
AUCo
fup
fup

80. Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
CLuint QH
fup

81. Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
CLuint
fup

82. Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kgQH

83. E QH fub fut CLT Vss t1/2 AUCo
High h n n
High n i n
High n n h

84. E QH fub fut CLT Vss t1/2 AUCo
Low h n n
Low n n h
Low n n h n